Heart failure represents the most prevalent cause of morbidity and mortality in the industrialized countries. Familial dilated cardiomyopathy (DCM) is the most common cause of heart failure in the US and worldwide. Recent advances in sequencing technology have further enabled the discovery of 33 known inherited mutations associated with DCM. Of these, more than 80% can be found in 7 genes, namely LMNA, MYH6, MYH7, MYPN, TNNT2, SCN5a, and MYBPC3. The logical next step is to study the correlation between genotype and the mechanistic basis behind the diseases. However, these studies have been hindered by the lack of appropriate disease models. In this proposal, I will generate human induced pluripotent stem cell- derived cardiomyocytes (hiPSC-CMs) from patients with DCM as disease models and perform detailed and mechanistic analyses to determine the functional and molecular phenotypes of DCM. Specifically, hiPSCs will be derived from healthy control and three family cohorts with inherited mutations in MYH6, TNNT2, and MYBPC3. These hiPSC lines will then be differentiating into cardiomyocytes. Next, the differentiated hiPSC- CMs from control and DCM patients will be compared by examining the morphology and myocyte architecture, electrophysiology, cellular mechanics, and gene expression profile. Finally, I will examine the response of the hiPSC-CMs from control and patient cohorts to pharmacologic treatment and gene therapy. In summary, these studies should pave the way to enhance our ability to perform future high-throughput drug screening, evaluate gene and cell therapies, and assess potential novel therapies of DCM. PUBLIC HEALTH RELEVANCE: Familial dilated cardiomyopathy (DCM) is the most common cause of heart failure and places a tremendous burden on the healthcare system in the US and worldwide. Investigators have attempted to study its mechanistic basis by correlating genotype with clinical phenotype expression. However, these studies have been severely hampered by the inaccessibility of human cardiomyocytes. In this proposal, I will utilize human induced pluripotent stem cell-derived cardiomyocytes as disease models for familial dilated cardiomyopathy. This strategy will enable us to better understand the mechanism behind the disease and dramatically enhance our ability to perform future high-throughput drug screening, evaluate gene and cell therapies, and assess potential novel therapies of familial dilated cardiomyopathy.